Monosomy 7 in t(9;22)-negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case.
Monosomy 7 in t(9;22)-negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case.
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DOI：
10.1016/j.cancergencyto.2006.12.011
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发表时间：
2007-07
影响因子：
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通讯作者：
A. Zeidan;S. Kakati;B. Anderson;M. Barcos;M. Wetzler
中科院分区：
文献类型：
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作者：
A. Zeidan;S. Kakati;B. Anderson;M. Barcos;M. Wetzler
一名33岁的白色女性于2004年12月被诊断为t（9; 22）阳性慢性髓细胞白血病（CML），并开始接受伊马替尼治疗，每日400 mg。治疗8个月后，患者仅获得轻微的细胞遗传学缓解，因此将伊马替尼增加至每日600 mg。患者随后发生III级血小板减少症，尽管降低伊马替尼剂量，但仍持续存在。因此，她于2005年10月入组口服尼洛替尼400 mg每日两次的II期剂量递增研究。患者对尼洛替尼有反应，出现轻度血小板减少症，但随着她开始出现细胞遗传学反应，骨髓中开始出现具有单体7（45，XX，-7）的原发异常克隆和发育异常变化（图）。因此，在2006年9月，该患者停用尼洛替尼，计划改用达沙替尼，并评估异基因干细胞移植。据我们所知，这是第一例报告的单体7出现在t（9; 22）-阴性细胞在伊马替尼耐药的CML患者在尼洛替尼治疗。在化疗[1]、干扰素[2]和伊马替尼治疗后约2%-17%的患者中很少报告t（9; 22）阴性细胞出现细胞遗传学畸变[3-7]。这些患者很少发生骨髓增生异常综合征（MDS）或急性髓性白血病（AML）;尤其是7号单体性患者[综述见7]。解释这种异常克隆出现的机制尚不清楚。据推测，t（9; 22）-阴性克隆可能早于获得t（9; 22）易位在CML发病机制的两个步骤。另一个密切相关的解释[5]是在患者的造血受到遗传损伤后出现了几个异常克隆。这些克隆之一携带t（9; 22），并处于增殖优势，因此掩盖了潜在的克隆多样性。伊马替尼（在我们的病例中为尼洛替尼）治疗所施加的选择性压力可以抑制具有t（9; 22）的细胞的增殖，这使得单体7克隆生长。这可能解释了伊马替尼治疗产生的t（9; 22）阴性克隆频率高于干扰素治疗，因为伊马替尼通常比干扰素更有效抑制t（9; 22）阳性克隆[6]。的
A 33-year-old white female was diagnosed with t (9; 22)-positive chronic myeloid leukemia (CML) in December 2004 and was started on imatinib at 400 mg daily. She achieved only minor cytogenetic response after eight months of treatment and therefore imatinib was increased to 600 mg daily. The patient then developed grade III thrombocytopenia that persisted despite reducing the imatinib dose. She was therefore enrolled on a phase II dose-escalation study of oral nilotinib 400 mg twice daily on October 2005. The patient responded to nilotinib with mild thrombocytopenia but as she started to develop cytogenetic response, de novo abnormal clone with monosomy 7 (45, XX,-7) and dysplastic changes started to appear in the marrow (Figure). Therefore, in September 2006 the patient taken off nilotininb with plans to switch to dasatinib and evaluate for allogeneic stem cell transplantation.To the best of our knowledge, this is the first case report of monosomy 7 arising in t (9; 22)-negative cells in an imatinib-resistant CML patient during nilotinib therapy. The appearance of cytogenetic aberrations in t (9; 22)-negative cells has been rarely reported following chemotherapy [1], interferon [2] and in approximately 2% to 17% of patients following imatinib therapy [3–7]. Few of these patients developed myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML); especially those with monosomy 7 [reviewed in 7]. The mechanisms to explain the emergence of such abnormal clones are not clear. It was postulated that the t (9; 22)-negative clone may have predated the acquisition of the t (9; 22) translocation in a two-step mechanism for CML pathogenesis. Another closely-related explanation [5] is the presence of several abnormal clones after the patient’s hematopoiesis has been subjected to genetic damage. One of these clones carries the t (9; 22) and is at a proliferative advantage therefore masking the underlying clonal diversity. The selective pressure applied by imatinib, or nilotinib in our case, therapy could suppress the proliferation of cells with t (9; 22) which allows the monosomy 7 clone to grow. This may explain the higher frequency of t (9; 22)-negative clones arising in response to therapy with imatinib than with interferon, as imatinib is generally more effective in suppressing the t (9; 22)-positive clone than interferon [6]. The